Process for manufacturing symmetrical diesters of bicyclo[3.3.0]-octanedione dicarboxylic acid

ABSTRACT

The invention concerns a process for manufacturing diesters of bicyclo[3.3.0]-octane dicarboxylic acid having general formula (I), where R 1  is a straight-chain or branched-chain alkyl group with 1 to 10 C atoms. The process is charaterized by the fact that a 2-cyclopentenone derivative having general formula (III), where R 2  is a hydrogen atom or a straight-chain or branched-chain alkyl group with 1 to 10 C atoms, which can be substituted, if necessary, by a phenyl group, is converted in the presence of a base with a diester of aceton dicarboxylic acid having formula (IV), where R 1  has the meaning given above.

BACKGROUND OF THE INVENTION

The invention relates to a new process for the production of symmetricalbicyclo[3.3.0]octanedione dicarboxylic acid diesters. Optically active6a-carba-prostacyclin and especially some compounds derived from it havea therapeutic use as stable analogs of the natural prostacyclin (PGI₂)[R. C. Nickolsen, M. H. Town, H. Vorbrueggen: Prostacyclin-Analogs,Medicinal Research Reviews, Vol. 5, No. 1, pp. 1-53 (1985)]. Thesyntheses specified in this recent survey are long and lead partly onlyto racemic carbacyclins. The syntheses, which lead to carbacyclins inthe absolute configuration corresponding to the natural PGI₂, areespecially expensive. The reason for this is that easily accessiblesuitable initial materials are achiral and the optical activity must beintroduced in the course of the synthesis only in intermediate stagessuitable for this purpose.

It is known that symmetrical prochiral dicarboxylic acid diesters ofprostacyclin and carbacyclin intermediate stages can be saponified anddecarboxylated enantioselectively to the monocarboxylic acid esters invery good yields, if enzymes, especially alpha-chymotrypsin, are usedfor this purpose (DE 36 38 760.6). ##STR1##

Symmetrical diester I used as initial material for this process isproduced, according to literature methods, from4-acetoxy-2-cyclopenten-1-one and acetone dicarboxylic acid ester [V.Osterthun and E. Winterfeldt, Chem. Ber. 11, 146 (1977) M. Harre, P.Raddatz, R. Walenta and E. Winterfeld, Angew, Chem. 94, 496 (1982)]. Inboth publications the acetoxy group in the 4-acetoxy-2-cyclopenten-1-oneis stressed as the leaving group necessary for the reaction. But theproduction of 4-acetoxy-2-cyclopenten-1-one proves to be especiallyexpensive and, in addition, uneconomical. Up to now no economicalsynthesis has been found for this purpose and it has been necessary toresort to the expensive initial materials 4-bromo-2-cyclo-penten-1-oneand silver racemate.

SUMMARY OF THE INVENTION

It has now been found that the above-named prochiral, symmetricaldicarboxylic acid diesters I can be produced in very good yields fromthe easily available 4-hydroxy-2-cyclopenten-1-one [P. G. Baraldi etal., Synthesis 1986, 781; K. Ogura et al., Tetr. Lett. 1976, 759] or4-tert-butoxy-2-cyclopenten-1-one or 4-cumyloxy-2-cyclopenten-1-one [S.Takano et al., Chem. Pharm. Bull. 34 (8), 3445 (1986); S. Takano et al.,Heterocycles 16, 605 (1981)] and acetone dicarboxylic acid esters.

The invention is suitable for the economical production of symmetricalprochiral diesters of general formula I.

Therefore the invention relates to a process for the production ofsymmetrical bicyclo[3.3.0]octane dicarboxylic acid diesters of generalformula I, ##STR2## in which R₁ represents a straight-chain orbranched-chain alkyl group with 1-10 C atoms, characterized in that a4-hydroxy or 4-alkoxy-2-cyclopenten-1-one of general formula III##STR3## in which R₂ can be a hydrogen atom or a straight-chain orbranched-chain alkyl group with 1-10 C atoms, which optionally can besubstituted by a phenyl group, is reacted with acetone dicarboxylic aciddiesters of formula IV, ##STR4## in which R₁ has the above-mentionedmeaning, in the presence of a base.

Potassium carbonate, sodium carbonate or a tertiary amine such asdiisopropylethylamine can, for example, be used as a base for the aboveprocess. The reaction is performed at -60° C. to +60° C., preferably 0°to 40° C. Methanol, ethanol, isopropanol, methylene chloride,tetrahydrofuran, among others, can be used as solvents or as solventmixtures.

The radical methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl,isohepty, n-octyl, isooctyl, n-nonyl, n-decyl among others are suitableas straight-chain or branched-chain alkyl radical with 1-10 C atoms. Thealkyl radicals with 1-6 C atoms are preferred, which can be substitutedby a phenyl radical. There can be mentioned, e.g., benzyl, phenethyl,cumyl, etc.

The compounds of formula I produced according to the process of theinvention are used for the production of pharmacologically effectiveprostacyclin derivatives.

The compounds of general formula I can be used for the production ofpharmacologically effective carbacylin derivatives [in this connectionsee R. C. Nickolson, M. N. Town and H. Vorbrueggen. Medicinal ResearchReview 5, 1 (1985) and P. A. Aristoff in Advances in Prostaglandin,Thromboxane and Leukotriene Research. Vol. 15 (1985))].

Starting from 2,4-bismethoxycarbonyl-bicyclo[3.3.0]octane-3,7-dione, theactive ingredient Iloprost is reached, for example, in a multistagesynthesis. Enyntioselective, enzymatic saponification, for example withalpha-chymotrypsin, yields according to DE 36 38 760.6 the opticallyactive monoester IIa. ##STR5##

After regioselective protection of the carbonyl group in IIa with formicacid ethyl ester in the presence of 2,2-dimethyl-1,3-diol and acatalytic amount of p-toluenesulfonic acid, IIb is reduced with sodiumboron hydride in ethanol to alcohol V. Silyl ether formation (VI) andthen reduction with diisobutylaluminum hydride in toluene at -70° C.yields aldehyde VII. which, with 3-methyl-2-oxo-hept-5-in phosphonicacid dimethyl ester and sodium hydride, is condensed toalpha,beta-unsaturated ketone VIII. Reduction of ketone VIII to alcoholIX, then protecting group cleavage to diol X and tetrahydropyranyl etherformation yields ketone XI, which after Wittig reaction with the ylenfrom 4-carboxybutyltriphenylphosphonium bromide and subsequentprotecting group cleavage with aqueous acetic acid is converted into thecarbacyclin derivative Iloprost.

The following embodiments serve to explain the process according to theinvention but without limiting it.

EXAMPLE 1 2,4-Bismethoxycarbonyl-bicyclo[3.3.0]octane-3,7-dione

A solution of 66 g of 4-tert-butoxy-2-cyclopenten-1-one and 72.1 g ofacetone dicarboxylic acid ester in 165 ml of methanol is added at 24° C.to a suspension of 80.1 g of potassium carbonate in 670 ml of methanoland stirred for 23 hours at 25° C. under argon. Then it is acidifiedwith 30% citric acid solution to pH 4, diluted with water and extractedfive times with methylene chloride. The organic phase is washed threetimes with brine, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel. 64 g of the title compound as colorless oil is eluted withethyl acetate/hexane.

IR (CHCl₃): 3022, 2962, 1740, 1665, 1624, 1445/cm.

The initial material for the above title compound is produced asfollows:

(1a) 4-tert-Butoxy-2-cyclopenten-1-one

90 ml of Jones reagent (chromium trioxide in sulfuric acid) is instilledat -30° C. in a solution of 64.7 g of 4-tert-butoxy-2-cyclopenten-1-ol(produced from cyclopentadiene according to S. Takano et al.,Heterocycles, 16, 605 (1981) in 750 ml of acetone and stirred for 20minutes at -30° C. Then 50 ml of isopropyl alcohol is instilled, dilutedwith ether and shaken several times with water. It is dried with sodiumsulfate and concentrated by evaporation in a vacuum. The residue isused, without further purification, in the condensation reactionaccording to example 1.

EXAMPLE 2 2,4-Bismethoxycarbonyl-bicyclo[3.3.0]octane-3,7-dione

A solution of 13.7 g of 4-hydroxy-2-cyclopent-1-one (for example,produced from 2-methylfuran according to v. Clauson-Kas et al., Actachem. scand. 1947, 619 or Synthesis 1986, 781) and 25.36 ml of acetonedicarboxylic acid diethyl ester in 42 ml of ethanol is instilled in astirred solution of 27 g of potassium carbonate in 116 ml of ethanol at0° C. under argon, stirred for 1 hour at 0° C. and 24 hours at 25° C. Itis concentrated by evaporation in a vacuum, 200 ml of water is added, itis acidified with 20% citric acid solution to pH 4, extracted withmethylene chloride and the organic extract is washed with brine. It isdried on magnesium sulfate and concentrated by evaporation in a vacuum.The residue is purified by chromatography on silica gel. 28 g of thetitle compound as colorless oil is eluted with ethyl acetate/hexane.

IR (CHCl₃): 3021, 2960, 1740, 1665, 1624, 1446/cm.

EXAMPLE 3 2,4-Bismethoxycarbonyl-bicyclo[3.3.0]octane-3,7-dione

A solution of 1 g of 4-cumyloxy-2-cyclopenten-1-one an 0.83 g of acetonedicarboxylic acid ester in 1.9 ml of methanol is added to a suspensionof 900 mg of potassium carbonate in 7.5 ml of methanol at 25° C. andstirred for 24 hours at 25° C. under argon. It is then acidified with30% citric acid solution to pH 4, diluted with water and extracted fivetimes with methylene chloride. The organic phase is washed three timeswith brine, dried on sodium sulfate and concentrarted by evaporation ina vacuum. The residue is purified by chromatography on silica gel. 0.85g of the title compound as light pink oil is eluted with ethylacetate/hexane mixtures.

IR (CHCl₃): 3021, 2960, 1740, 1665, 1624, 1446/cm.

The initial material for the above title compound is produced asfollows:

(3a) 4-Cumyloxy-2-cyclopenten-1-one

6 ml of Jones reagent is instilled in a solution of 4.1 g of4-cumyl-2-cyclopenten-1-ol (produced from cyclopentadiene according toS. Takano, Chem. Pharm. Bull. 34, 3445 (1986) in 50 ml of acetone at-30° C. and stirred for 20 minutes at -30° C. Then 6 ml of isopropanolis instilled, diluted with ether and shaken several times with water. Itis dried with sodium sulfate and concentrated by evaporation in avacuum. After filtering of the residue on silica gel with hexane/ethylacetate mixtures, 3.81 g of 4-cumyloxy-2-cyclopenten-1-one is obtainedas colorless oil.

I claim:
 1. A process for the production of a bicyclo[3.3.0]octane dicarboxylic acid diester of general formula I, ##STR6## in which R₁ represents a straight-chain or branched-chain alkyl group with 1-10 C atoms, characterized in that a 2-cyclopentenone derivative of general formula III ##STR7## in which R₂ can be a hydrogen atom or a straight-chain or branched-chain alkyl group with 1-10 C atoms, which optionally can be substituted by a phenyl group, are reacted with an acetone dicarboxylic acid diester of formula IV, ##STR8## in which R₁ has the above-mentioned meaning, in the presence of a base.
 2. A process according to claim 1, wherein R₁ is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertbutyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl or n-decyl.
 3. A process according to claim 1, wherein R₂ is substituted by a phenyl group.
 4. A process according to claim 1, wherein the phenyl group is benzyl, phenethyl or cumyl.
 5. A process according to claim 1, wherein the base is potassium carbonate, sodium carbonate, or a tertiary amine.
 6. A process according to claim 1, wherein the process is carried out in the presence of a solvent.
 7. A process according to claim 6, wherein the solvent is methanol, ethanol, isopropanol, methylene chloride or tetrahydrofuran or mixtures thereof.
 8. A process according to claim 1, wherein the reaction is carried out at -60° C. to 60° C.
 9. A process according to claim 8, wherein the process is carried out at 0° to 40° C. 